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Review
. 2018 Apr 10;419:20-26.
doi: 10.1016/j.canlet.2018.01.033. Epub 2018 Jan 12.

Autophagy and T Cell Metabolism

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Free PMC article
Review

Autophagy and T Cell Metabolism

Samuel D Dowling et al. Cancer Lett. .
Free PMC article

Abstract

Autophagy, a highly conserved catabolic process that involves the degradation and recycling of intracellular components in the lysosome, has emerged as a key process in the maintenance of T cell homeostasis and the regulation of T cell differentiation and function. In this review, we provide an overview of the mechanisms that mediate the regulation of autophagy in T cells and discuss different cellular processes that are under the control of autophagy in CD4+ and CD8+ T cells. A special emphasis is placed on the role that autophagy plays in the modulation of T cell metabolism and the consequences of this regulation on functional states and programs of differentiation in specific T cell populations.

Figures

Figure 1
Figure 1. Mechanism of autophagy in T cells
TCR-induced expression of IL-2 leads to activation of the IL-2 receptor (IL-2r), which leads to the activation of autophagy in T helper cells in a JAK1.3-dependent manner. The initiation of autophagy and formation of the limiting membrane and then phagophore are driven by two complexes: the ULK-complex—ULK/FIP200/Atg101/Atg13; and the Beclin-1/Vps34 complex (class III phosphatidylinositol-3-kinase complex (PI3KC3) containing Beclin-1, Vps34, Vps15, Atg14 and Ambra1). Two cascades of ubiquitin-like conjugation systems regulate the elongation and maturation of the de novo formed double-membrane vesicle to form the autophagosome, which eventually fuses with the lysosome to degrade cargo. The lipidation of LC3 to PE allows association with the membranes of the autophagosome. This allows specific substrates to be targeted to the autophagosome by interaction with LC3 via LC3-interacting motifs as well as autophagic cargo receptors with LC3-interacting regions. The specific sequestration and degradation of substrates complements in-bulk mechanisms of degradation of organelles, macromolecules (i.e. proteins, lipids, glycogen), and other cellular components.
Figure 2
Figure 2. Roles of autophagy in T cells
Engagement of the TCR and CD28 signaling pathways is required for full activation of T cells, which can be further augmented by signaling through the IL-2r. Autophagy is maintained at basal levels in naïve and resting T cells and the cargo of autophagosomes largely consists of organelles, such as mitochondria (1), which is an important quality control mechanism. TCR- and IL-2r-signaling induce autophagy. Upon activation the cargo nature switches to mostly cytosolic components, and activation-induced degradation of specific proteins (p27, caspases, Bim or Bcl10) has been described to control proliferation, survival and activation. Important roles of Autophagy have been reported in the regulation of cell homeostasis (2); TCR signaling transduction (3); the breakdown of macromolecules to recycle cellular building blocks and generate signaling metabolites (4); and the regulation of T cell metabolism (5). In addition, macroautophagy has been shown to be necessary for CD4+ T cell activation, cell survival, and proliferation (6), differentiation of specific CD4+ T helper subsets, (7), enforcing Treg lineage stability (8), and for generation of CD8+ memory T cells (9).

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